Structural and Functional Interaction of Δ<sup>9</sup>-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Huang, Huan; McIntosh, Avery L.; Martin, Gregory G.; Dangott, Lawrence J.; Kier, Ann B.; Schroeder, Friedhelm

doi:10.1021/acs.biochem.8b00744

Cited by 11 publications

(11 citation statements)

References 96 publications

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“…Our data confirm recent reports that FABP1 binds the phytocannabinoids THC and CBD with moderately high affinities, as well as the major THC metabolites 11-OH-THC and THC-COOH with comparatively reduced affinities 16,48 . The synthetic THC-COOH analog AJA was also found to interact with FABP1.…”

Section: Discussionsupporting

confidence: 91%

“…We observed reduced rates of THC biotransformation in primary hepatocytes derived from FABP1-KO mice, suggesting a functional significance of FABP1 within the liver. However, it is noteworthy that another group recently reported an overall increase in THC metabolites found within THC-treated FABP1-KO hepatocytes 48 . This apparent discrepancy may potentially be explained through methodological differences in the hepatocyte culture confluency used for experiments, or in the methods of lipid extraction and quantification of metabolites.…”

Section: Discussionmentioning

confidence: 93%

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FABP1 controls hepatic transport and biotransformation of Δ9-THC

Elmes

Prentis

McGoldrick

et al. 2019

Sci Rep

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The increasing use of medical marijuana highlights the importance of developing a better understanding of cannabinoid metabolism. Phytocannabinoids, including ∆ 9 -tetrahydrocannabinol (THC), are metabolized and inactivated by cytochrome P450 enzymes primarily within the liver. The lipophilic nature of cannabinoids necessitates mechanism(s) to facilitate their intracellular transport to metabolic enzymes. Here, we test the central hypothesis that liver-type fatty acid binding protein (FABP1) mediates phytocannabinoid transport and subsequent inactivation. Using X-ray crystallography, molecular modeling, and in vitro binding approaches we demonstrate that FABP1 accommodates one molecule of THC within its ligand binding pocket. Consistent with its role as a THC carrier, biotransformation of THC was reduced in primary hepatocytes obtained from FABP1-knockout (FABP1-KO) mice. Compared to their wild-type littermates, administration of THC to male and female FABP1-KO mice potentiated the physiological and behavioral effects of THC. The stark pharmacodynamic differences were confirmed upon pharmacokinetic analyses which revealed that FABP1-KO mice exhibit reduced rates of THC biotransformation. Collectively, these data position FABP1 as a hepatic THC transport protein and a critical mediator of cannabinoid inactivation. Since commonly used medications bind to FABP1 with comparable affinities to THC, our results further suggest that FABP1 could serve a previously unrecognized site of drug-drug interactions.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 93%

FABP1 controls hepatic transport and biotransformation of Δ9-THC

Elmes

Prentis

McGoldrick

et al. 2019

Sci Rep

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“…Indirect measurements of ligand binding for FABPs have been a common approach for estimating binding affinities for FABPs (Schug et al, 2007;Smathers and Petersen, 2011;Kaczocha et al, 2012;Elmes et al, 2015Elmes et al, , 2019Huang et al, 2016Huang et al, , 2018Schroeder et al, 2016). Fluorescence displacement assays using fluorescent probes such as ANS or fluorophore conjugated fatty acids such as 11-(dansylamino)undecanoic acid (DAUDA) and nitrobenzoxadiazole (NBD)-stearate are commonly used due to the low intrinsic fluorescence of FABPs, and the lack of measurable fluorescence from fatty acid ligands upon FABP binding.…”

Section: Fluorescence Displacement Assaysmentioning

confidence: 99%

Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition

Yabut

Isoherranen

2023

Drug Metab Dispos

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The family of intracellular lipid binding proteins (iLBPs) is comprised of sixteen members of structurally related binding proteins that have ubiquitous tissue expression in humans. iLBPs collectively bind diverse essential endogenous lipids and xenobiotics. iLBPs solubilize and traffic lipophilic ligands through the aqueous milieu of the cell. Their expression is correlated with increased rates of ligand uptake into tissues and altered ligand metabolism. The importance of iLBPs in maintaining lipid homeostasis is well established. Fatty acid binding proteins (FABPs) make up the majority of iLBPs and are expressed in major organs relevant to xenobiotic absorption, distribution and metabolism. FABPs also bind a variety of xenobiotics including non-steroidal anti-inflammatory drugs, psychoactive cannabinoids, benzodiazepines, antinociceptives and peroxisome proliferators. FABP function is also associated with metabolic disease making FABPs currently a target for drug development. Yet, the potential contribution of FABP binding to distribution of xenobiotics into tissues and the mechanistic impact iLBPs may have on xenobiotic metabolism is largely undefined. This review examines the tissue specific expression and functions of iLBPs, the ligand binding characteristics of iLBPs, their known endogenous and xenobiotic ligands, methods for measuring ligand binding and mechanisms of ligand delivery from iLBPs to membranes and enzymes. Current knowledge of the importance of iLBPs in affecting disposition of xenobiotics is collectively described. Significance StatementThe data reviewed here show that FABPs bind many drugs and suggest that binding of drugs to FABPs in various tissues will affect drug distribution into tissues. The extensive work and findings with endogenous ligands suggest that FABPs may also alter the metabolism and transport of drugs. This review illustrates the potential significance of this understudied area.

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“…In contrast to this, another study from the same group was able to demonstrate that AEA and 2-AG levels were unaltered and OEA and PEA were decreased in brains of female FABP1 knockout mice as compared to wild-type animals (Martin et al, 2016a). In addition, Δ 9 -THC and Δ 9 -THC-OH, as well as downstream metabolites of Δ 9 -THC such as Δ 9 -THC-COOH and Δ 9 -THC-CO-glucuronide were found as binding partners of hepatic FABP1 (Huang et al, 2018). Furthermore, a potentiated uptake of AEA was described for FABP5-overexpressing neuroblastoma cells (Kaczocha et al, 2009).…”

Section: Transport Proteinsmentioning

confidence: 99%

Modulation of the Endocannabinoid System as a Potential Anticancer Strategy

2019

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Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N -arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the G i/o protein-coupled transmembrane cannabinoid receptors CB 1 and CB 2 . As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O -arachidonoylethanolamine, N -arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.

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Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Cited by 11 publications

References 96 publications

FABP1 controls hepatic transport and biotransformation of Δ9-THC

FABP1 controls hepatic transport and biotransformation of Δ9-THC

Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition

Modulation of the Endocannabinoid System as a Potential Anticancer Strategy

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Structural and Functional Interaction of Δ9-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)

Cited by 11 publications

References 96 publications

FABP1 controls hepatic transport and biotransformation of Δ9-THC

FABP1 controls hepatic transport and biotransformation of Δ9-THC

Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition

Modulation of the Endocannabinoid System as a Potential Anticancer Strategy

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Product

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Structural and Functional Interaction of Δ⁹-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1)